Poor Outcomes for Patients with Metastatic Castration-resistant Prostate Cancer with Low Prostate-specific Membrane Antigen (PSMA) Expression Deemed Ineligible for 177Lu-labelled PSMA Radioligand Therapy
Introduction
Despite advances in systemic therapies, men presenting with metastatic prostate cancer have poor outcomes, with overall survival (OS) of <5 yr [1]. Progression to metastatic castration-resistant prostate cancer (mCRPC) reduces OS to <3 yr [2], which remains relatively short despite the introduction of several life-prolonging therapies in the last few years [3], [4], [5], [6].
Prostate-specific membrane antigen (PSMA) is overexpressed in prostate cancer cells, with higher expression in higher-grade and metastatic castration-resistant disease [7]. PSMA-based positron emission tomography (PET)/computed tomography (CT) imaging has rapidly emerged as a potential new standard of care for imaging prostate cancer, with images demonstrating striking tumour-to-background contrast [8]. However, evolving experience has demonstrated that some patients with high-grade disease have either no or low PSMA expression at baseline, whereas other patients with initially highly PSMA-avid disease develop sites of low PSMA-expressing metastatic disease over time. These observations have significant implications for theranostic approaches targeting PSMA. Radionuclide therapy targeting the PSMA receptor has been increasingly used since 2013, and retrospective studies indicate that this therapy is both efficacious and tolerable [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19] and may improve survival [13], [15], [20], [21], [22].
Our centre performed a phase 2 trial of 177Lu-PSMA-617 to evaluate the efficacy and safety profile of this radioligand in men with mCRPC who have failed conventional therapy, including docetaxel chemotherapy and second-generation hormonal therapy involving enzalutamide or abiraterone [23]. We demonstrated that treatment had a high response rate and low toxicity and resulted in a marked reduction in pain alongside improvements in quality of life. We also demonstrated that the dose delivered to tumour correlated with prostate-specific antigen (PSA) response [24]. In the study we performed 18F-fluorodeoxyglucose (FDG) PET/CT alongside 68Ga-PSMA-11 PET/CT at baseline to characterise imaging phenotypes and select patients who were best suited for 177Lu-PSMA-617 therapy. This patient selection strategy was adapted from our experience with peptide receptor radionuclide therapy in patients with neuroendocrine tumours. In these patients, we frequently visualise tumour heterogeneity, whereby FDG-avid disease occurs with low or absent somatostatin receptor expression in patients with advanced disease. These represent sites of aggressive disease that cannot be effectively targeted with radionuclide therapy and, in our experience, these patients have a poor prognosis. Accordingly, in the design of our phase 2 study, we excluded patients with either low PSMA expression or sites of FDG-positive disease with low or absent PSMA expression (discordant FDG-avid disease). In the present study, we analyse the clinicopathological features and outcomes for these patients who were screened but not treated owing to these factors.
Section snippets
Study design
This investigator-initiated, single-centre, phase 2 trial recruited 50 patients suitable for 177Lu-PSMA-617 therapy, including an initial 30-patient cohort and followed by a 20-patient expansion. Patient screening occurred from August 2015 to June 2017. The trial inclusion and exclusion criteria are shown in Table 1. As part of the screening phase of the study, all patients underwent 68Ga-PSMA-11 and 18F-FDG PET/CT following a 60-min uptake phase (GE Discovery 710, 690 or Siemens Biograph 64).
Results
Sixteen patients (median age 71 yr, range 58–88) who were screened for the trial were excluded on the basis of low PSMA expression or discordant FDG-avid disease; these patients met other study inclusion/exclusion criteria. Eleven patients had a Gleason score ≥8. The median PSA doubling time was 2.1 mo at screening. All patients progressed on docetaxel chemotherapy, and seven (44%) had progressed after second-line cabazitaxel chemotherapy. All patients except for one progressed after abiraterone
Discussion
Our study cohort of men with advanced mCRPC and either low PSMA expression or discordant FDG-avid had poor prognosis, with median OS of 2.5 mo. This compares to median OS of 13.5 mo in our initial 30-patient cohort who received 177Lu-PSMA-617 therapy; at this time there was insufficient follow-up for the expanded 50-patient cohort to provide robust data [23]. Comparisons of the baseline characteristics for these two groups are limited by the small sample size, but are broadly comparable, as
Conclusions
For patients with mCRPC that progressed after conventional therapies, low PSMA expression or discordant FDG-avid disease identifies a patient cohort with poor prognosis and short survival. Addition of FDG PET/CT to identify discordant disease appears to assist in optimal selection of patients most likely to benefit from PSMA-targeted radionuclide therapy. We are further exploring this in a randomised phase 2 trial of 177Lu-PSMA-617 (NCT03392428). The use of combined PSMA and FDG PET/CT may have
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